Renal Artery Stenosis in the Patient with Hypertension: Prevalence, Impact and Management

Figures & data

Table 1 Functional Classification of ARAS in Association with Hypertension²⁶

Grade	Description
I	Asymptomatic ARAS with normotensive blood pressure and normal renal function
II	ARAS with well controlled hypertension using medical therapy and normal renal function
III	ARAS with uncontrolled hypertension despite optimal medical therapy or clinical signs of volume overload and abnormal renal function

Note: Data from Rocha-Singh et al.²⁶

Table 2 Imaging Modalities Utilized for Diagnosing ARAS^32–38

Imaging Test	Advantages	Disadvantages
Doppler Ultrasound (DUS)^Citation32	-able to pinpoint the exact location of ARAS -the degree of stenosis can be identified with direct visualization of renal arteries and doppler velocity measurements of blood flow -PSV > 200 cm/s has a 95% sensitivity and 90% specificity for renal artery stenosis >50% -utilized to follow up after PTRAS and monitor for restenosis	- insufficient evaluation of accessory renal arteries in overweight individuals - presence of bowel gases impairs visualization of the renal artery - the quality of study is dependent on the operator
Computerized Tomographic Angiography (CTA)^Citation33	- there is high spatial resolution and increased speed of image acquisition -the sensitivity is 94% and specificity is 93% for a renal artery stenosis lesion greater than 50%	- lack of information on renal flow or pressure distal to RAS -radiation exposure - risks associated with using iodinated contrast - there is increased risk of nephrotoxic effects of the contrast
Magnetic Resonance Angiography (MRA)^Citation33	- allow for visualization of the renal artery without the need for ionizing radiation -can obtain hemodynamic data such as, increased blood flow turbulence -can be used to evaluate in-stent restenosis -the sensitivity is 96% and specificity is 92% in detecting renal artery stenosis greater than or equal to 50%	- there is a risk of causing nephrogenic systemic fibrosis with gadolinium contrast in patients with severe renal insufficiency or dialysis dependency
Arterial Angiography^Citation34	- usually follows a positive non-invasive screening test first and is the gold standard for diagnosing ARAS -there is better accuracy in identifying hemodynamically significant stenosis via measurement of the translesional pressure gradient	- risks associated with the procedure include: vascular access related complications, embolization, radiation exposure, iodinated contrast related reaction and contrast induced nephropathy
BOLD MRI^Citation36	- an accurate way of monitoring renal tissue oxygenation and degree of renal hypoxia in ARAS by measuring levels of serum injury biomarkers in the draining renal vein -correlate with the severity of renal blood flow obstruction - can monitor therapeutic interventions or pretreatment with adjunct cellular based therapies for ARAS before renal revascularization is pursued	- its use is restricted to research setting presently
Dynamic Contrast Enhanced MRI^Citation35	- can measure single kidney glomerular filtration rate, tissue perfusion and vascularity which can better characterize the overall functionality of the kidney and determine directly irreversible renal parenchymal damage -it can be used to assess functional outcomes after renal artery revascularization	- affected by respiratory motion artifacts - the contrast agent has the potential of causing nephrotoxicity especially in patients with severe chronic kidney disease - there is a lack of standard imaging and analysis protocols
Intravascular Ultrasound (IVUS)^Citation37	- characterize renal artery plaque - well validated imaging modality to guide optimal stent implantation	- it is of low quality and low resolution imaging compared to optical coherence tomography (OCT) intravascular imaging -it is difficult to decipher fine details such as stent strut versus thrombus
Renal Frame Count^Citation38	- an intraprocedural tool that can assess and quantify perfusion of kidneys in determining the severity of ARAS and predict a clinical response after PTRAS	- there is risk of azotemia from the nephrotoxic effects of the contrast

Table 3 Physiologic Diagnostic Tests Used to Diagnose ARAS^39–41

Test	Advantages	Disadvantages
Plasma Renin Activity	-it can be used in procedural setting to predict which individuals with ARAS will have improvement in their resistant hypertension after PTRAS	- affected by physiological parameters (blood volume, sodium load, unilateral versus bilateral renal disease, age, race, sex and comorbidities) which can alter the circulating levels of renin -the test’s sensitivity is 57% and specificity is 66%
Captopril Renography	- provides functional data with regards to GFR reduction with ARAS with angiotensin converting enzyme inhibitor (ACE-I) compared to the increase GFR in contralateral side -measures the plasma aldosterone concentration (PAC), plasma renin concentration (ARC) and plasma renin activity (PRA) -Diagnosis of renovascular hypertension made by PAC/ARC >40 or PAC/PRA >200 -sensitivity of the test is 74% while the specificity is 59%	-it cannot specify anatomical location of renal artery lesion -not a reliable test in those with poor renal function and bilateral renal disease
Bilateral Renal Vein Renin Assay	-the renal vein renin ratio is the renin level of the ischemic kidney compared to the contralateral kidney which allows selection of individuals with hypertension and ARAS who may benefit from interventions -in 90% of the situations these individuals will respond to treatment	-high false positives and negatives, both are 67% -difficult to differentiate hypertensive individuals with unilateral and bilateral ARAS and many of them will have essential hypertension rather than renin-mediated therefore necessitating the use of additional studies (doppler ultrasound and catheter based renal arteriography)

Table 4 Comparison of Randomized Control Trials for OMT versus OMT and PTRAS in ARAS

Name of Clinical Trial	ASTRAL^Citation5 (806 Participants)	STAR^Citation6 (140 Participants)	CORAL^Citation7 (947 Participants)
Severity of ARAS	Any degree of ARAS (confirmed by DUS, CTA, MRA and renal angiography)	At least 50% ARAS (seen on CTA, MRA and renal angiography)	At least 80% ARAS (seen on DUS, CTA or MRA)
Inclusion Criteria of Blood Pressure	Uncontrolled or resistant hypertension	Stable BP <140/90 mmHg on medication	Systolic BP greater than 155 mmHg, on two anti-hypertensive medications
Inclusion Criteria of Renal Disease	Any degree of unexplained renal dysfunction	CrCl <80 mL/min/1.73 m^2	eGFR of less than 60 mL/min/1.73 m^2
Exclusion Criteria	-Surgical renal revascularization required or high likelihood will be needed within 6 months -Previous revascularization for renal artery stenosis -Nonatheromatous cardiovascular disease	-Proven cholesterol embolization at previous interventions -Any known cause of renal failure other than ischemic nephropathy -Pulmonary edema in the presence of bilateral renovascular disease in combination with intolerance of ACE-I or angiotensin-II antagonist defined as a decline in eCrCl > 20% -Myocardial infarction or cerebrovascular accident less than 3 months -Renal artery diameter < 4 mm	-Renal artery stenosis due to fibromuscular dysplasia -CKD from another cause besides ischemic nephropathy -CKD associated with a serum creatinine level greater than 4 mg/dL or kidney length less than 7 cm -Renal artery stenosis lesion that could not be treated with the use of a single stent
Follow-Up	34 months	24 months	43 months
Endpoints	Primary: change in renal function Secondary: blood pressure control, time to first renal event, time to first cardiovascular event and mortality	Primary: reduction in creatinine clearance greater than 20% compared to baseline Secondary: safety, cardiovascular morbidity and mortality	Primary: composite of cardiovascular or renal death, myocardial infarction, stroke, hospitalization for ADHF, progressive renal insufficiency and need for dialysis
Results	-The rate of progression of renal impairment was lower in the revascularization group.-Blood pressure readings decreased but without significant difference between the two groups.	Approximately 16% in the PTRAS group and 22% in the OMT alone group had a 20% or greater decrease in creatinine clearance.	-No significant difference in rate of primary end points or all cause mortality was seen.-There was a difference in systolic blood pressure seen in the PTRAS group.
Limitations	-Approximately 25% of study participants in each group had normal renal function at the entry of the trial. -Some participants identified as having 50–70% stenosis in actuality had stenosis of <50%. -There was a high complication rate (9% in the first 24 hours) after PTRAS. -It was a non-blinded trial so observer and selection bias was present. -Nearly 6% of the study participants crossed over from OMT to intervention group. -There was low power to detect difference in subgroups.	-Study participants were falsely identified with ARAS by non-invasive imaging and some did not require stenting. -Complication rates were high.	-Study participants were not medically optimized on their blood pressure medications. -Participants with severe ARAS were withdrawn from study. -ARAS was not confirmed to have hemodynamic significance. -Participants with mild stenosis were also included and randomized to PTRAS.

Table 5 Procedural Complications Seen with PTRAS⁵⁶

Procedural Complication	Percentage of Patients Affected
30 day mortality	1%
Worsening of renal function	4%
Acute renal failure	2%
Segmental kidney infarction	1–2%
Need for surgical intervention for either nephrectomy or salvage	2%
Groin hematoma and puncture site trauma	3–5%
Occlusion of the renal artery	2–3%
Symptomatic embolization	3%
Death	1%

Note: Data from Ruzsa et al.⁵⁶

Table 6 American College of Cardiology Appropriate Use Criteria for Treatment of ARAS

Clinical Scenario*	Percutaneous Renal Artery Stenting	Class and Level of Evidence
Sudden presentation of flash pulmonary edema	Appropriate	Class I, LOE B
Bilateral ARAS or a solitary viable kidney with ARAS along with declining renal function	Appropriate	Class IIa, LOE B
Failure to control blood pressure on three maximally treated medications (one of which is a diuretic)	May be appropriate	Class IIa, LOE B
Recurrent ADHF requiring hospitalization despite being on maximal medical treatment	May be appropriate	Class I, LOE B
Unilateral ARAS with declining renal function	May be appropriate	Class IIb, LOE C
ACS while being on OMT	May be appropriate	Class IIa, LOE B
Well controlled blood pressure on two or more antihypertensive medications	Rarely appropriate
Uncontrolled blood pressure on less than three antihypertensive medications	Rarely appropriate
Incidentally discovered unilateral ARAS (severe ARAS 70–99% stenosis or 50–69% stenosis with hemodynamic significance)	Rarely appropriate
Incidentally discovered bilateral ARAS or solitary kidney (severe ARAS 70–99% stenosis or 50–69% stenosis with hemodynamic significance)	Rarely appropriate
Unilateral ARAS, bilateral ARAS or a solitary kidney with borderline (50–69% stenosis without hemodynamic confirmation of severity)	Rarely appropriate

Notes: *Significant ARAS = moderate (50% −70%) ARAS with a resting/hyperemic translesional mean gradient of ≥10 mm Hg, systolic gradient ≥20 mm Hg/or severe (>70%) ARAS. Data from Bailey et al.⁵¹

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